Thrombophilia

1
Thrombophilia

• Dr Galila Zaher
• MRCPath
• Consultant Hematologist

2
Thrombophilia

• A disorder of the haemostatic mechanism with a
  predisposition towards thrombosis
• BUT Many patients with defects remain
  asymptomatic despite multiple challenges
• AND gt50 patients with TED will have no
  identifiable laboratory abnormality
• AND proven thrombophilic defect and a family
  history of TED are at greater risk of TED than
  individuals with no family history but a similar
  defect

3
Thrombophilia

• Patients with spontaneous venous thromboses,
  or of a severity that is out of proportion to a
  recognised stimulus

4
Venous Thromboembolic Disease

• Common , associated with considerable morbidity
  and mortality
• USA
• 11,000 pa clinically significant DVTs
• 250,000 hospitalisations annually due to
  VTED

5
Complications

• Risk of recurrence 2 years 17.5
• 5 years 24.6
• Fatal PE 150,000 pa
  
• 20-30 PM
• Commonest cause of death in pregnancy
• Post-phlebitic syndrome up to 20

6
Who to test?

• Thrombosis at an unusual site
• Recurrent thromboses
• Family history of thrombosis
• Age less than 40
• Recurrent miscarriages

7
Inherited Thrombophilia

• 1965 AT mutation identified Egeberg et al
• 1967 Dysfunctional fibrinogen Egeberg et al
• 1981 Protein C Griffin et al
• 1984 Protein S Comp et al
• 1993/4 APCr/FV L Dalhback/Bertina et
  al
• 1996 Prothrombin mutation Poort et
  al

8
Thrombophilia Prevalence
Risk factor Subjects with thrombosis () General population () Relative Risk of Thrombosis
Antithrombin 1 0.2 25-50
Protein C 3 0.3 10-15
Protein S 2-3 0.2 11
Factor V Leiden Hetero 20-50 3-15 3-8/80 Homo
Prothrombin 3' UTR mutation Hetero 6 2 3
9
Other Inherited Risk Factors

• Hyperhomocysteineaemia
• Dysfibrinogenaemias
• Factor VII ?/?
• Heparin Cofactor II
• Factor XII deficiency
• Disordered fibrinolysis
• Elevated PAI-1
• Plasminogen deficiency
• Thrombin Activatable Fibrinolytic Inhibitor (TAFI)

10
Anti-phospholipid antibodies
Risk factor Subjects with VTE () General population () RR of Thrombosis
Lupus anticoagulant 3-10 4 11
Anti-cardiolipin antibodies 3-10 4 3.2
OCP 21 6 4.2
Pregnancy 6.2 2.3 2.8
Previous VTED 14 2 8
11
Acquired

• Obesity
• Immobility (surgery/trauma)
• OCP/HRT
• Pregnancy/puerperium
• Haemoglobinopathies
• Myeloproliferative syndromes
• Hyperviscosity syndromes
• Cardiac failure

12
Acquired

• Chronic inflammatory disorders
• Klinefelters syndrome
• Behçets syndrome
• Malignancy
• Drug induced (e.g. HIT)
• TTP/HUS
• Nephrotic syndrome
• Protein S deficiency
• Inflammatory bowel disease

13
Thrombophilia and Laboratory Testing

• Diagnostic accuracy
• Clinical value of the tests
• Interpretation of results
• Tests frequently requested (and interpreted) by
  individuals who are not specialists in this area
• Laboratories frequently have no clinical
  information relating to the patient

14
Genetic Testing

• Reliable and reasonably robust
• National External Quality Assurance Schemes
  (NEQAS)
• Some incorrectly identified samples
• APCr low Factor V Leiden mutation confirms
• APCr normal No further testing
• Risk of VTED modest
• Do we seek informed consent for genetic testing?

15
Phenotypic Testing Accuracy

• Enormous variability in results
• NEQAS/ECAT data supports this
• Oral anticoagulants Protein C/S
• Inappropriate to base a diagnosis on a single
  result but how many times ?
• Incorrect information to patients may be falsely
  reassuring or result in inappropriate treatment

16
Antithrombin deficiency

• 24 patients with genotypically proven AT
  deficiency
• Heparin co-factor assay
• IIa substrateCorrectly identified all mutations
• Xa substrateCorrectly diagnosed only 50 cases
• NEQAS thrombophilia Survey March 2000
• Functional AT assays showed significant
  differences depending upon substrate

17
Laboratory Tests
15 heterozygous PC deficient patients had
normal PC activity and 5 normal relatives had
low PC activity
Heterozygotes
Normal relatives
18
Immediate Management

• No evidence that anticoagulation is less
  efficient with prothrombotic abnormalities
• Antithrombin deficiency Heparin resistance is
  rare type I can be efficiently anticoagulated ,
  antithrombin concentrates is not usually
  indicated
• PC and PS deficiencyWarfarin induced skin
  necrosis is rare
• Screening prior to initiating OAC therapy
  inappropriate
• LA,severe FXII deficiencyelevated Factor VIII
  levels difficult monitoring UFH

19
Intensity Or Duration Of Anticoagulation

• No randomised prospective studiesCurrent
  data/experience standard oral anticoagulant
  protocols
• No evidence that more intensive regimes or
  extended periods of anticoagulation are required
• BUT - APL/multiple inherited abnormalities
  including may be exceptions
• Risk of recurrence may be increased and extended
  periods of treatment may be required
• OACs Mortality 0.3-0.4
• Major bleed 2-3

20
Aggressive Thromboprophylaxis?

• RR increased but the absolute risk is small
• Thromboprophylaxis
• Asymptomatic No indication
• At-risk individuals high risk periods should
  be given
• Economy Class syndrome 90 have gt2 risk
  factors for thrombosis

21
Prothrombotic Abnormality OCP

• Thrombosis in women with inherited prothrombotic
  OCP is increased
• Family studies may be of value in establishing
  the risk of thrombosis if a genetic risk factor
  has been identified
• POP or progestagen-containing IUDs no increased
  risk of VTED
• Factor V Leiden OCP
• RR VTED 35/50-fold increase

22
Prothrombotic Abnormality OCP

• Avoid
• In women with history of TED
• 1st-degree relative with TED
• in women with multiple genetic defects
• Asymptomatic women with identified genetic risk
  factors - not absolute contraindication OCP

23
Prothrombotic Abnormality HRT

• HRT increases risk of TED 3-fold
• Risk highest in the initial 12 ms of treatment
• Synergy between HRT and thrombophilia
• Use with caution in women with a PMH of TED
• EVTET study HRT 10.7 incidence of VTED
• Placebo 2.3
• Asymptomatic women with identified genetic risk
  factors - not an absolute contraindication to HRT

24
Thromboprophylaxis In Pregnancy

• Risk of VTED increased in pregnancy
• Genetic risk factor
• Multiple pregnancy
• Advanced maternal age
• Prolonged bed-rest
• Previous thrombotic history
• Recurrent miscarriages
• Routine thromboprophylaxis is not indicated in
  all women with thrombophilia

25
Thrombophilia Arterial Disease

• No good evidence
• Anti-phospholipid syndrome
• Hyperhomocysteineaemia
• Factor V Leiden/Prothrombin mutation - Possible
  synergistic interaction with other risk factors

26
Summary

• Increasing enthusiasm for thrombophilia testing
• Concerns about accuracy and interpretation
• Lack of evidence-based data to aid management
• Are we providing patients and clinicians with
  inaccurate information that leads to false
  reassurance or alternatively creates panic and
  results in inappropriate treatment?

27

• Genetic defect NO TED
• TED 50 No lab abnormality
• Lab abnormality FH gtlab with NO FH

28
Other Inherited Risk Factors

• Histidine rich glycoprotein
• Elevated FVIII/FX/FXI
• Thrombomodulin mutations
• EPCR mutations
• Tissue Factor Pathway Inhibitor (TFPI)
• Factor V Cambridge
• Factor XIII (Val234Leu)
• Platelet glycoprotein receptor polymorphisms

29
Thrombophilia

• Thrombosis is a multi-factorial disease
• Multiple genetic risk factors increase the risk
  of TED
• In the majority screen for only the common
  inherited/acquired prothrombotic abnormalities
• 50 of patients with TED have no evidence of
  prothrombotic abnormalities

30
Management of thrombophilia

• Dr Galila Zaher
• MRCPath
• Consultant Hematologist

31
BLOOD CLOTTING

• Blood clotting interactions
• Plasma protein clotting factors
• Vascular endothelium

Platelets
32
Hemostasis
Hemostasis
Subendothelial matrix
Subendothelial matrix
Hemostatic plug
Hemostatic plug
Endothelial cell
Endothelial cell
WBC
WBC
WBC
WBC
Fibrin
RBC
Platelets
Fibrin
RBC
Platelets
33
COAGULOPATHIES

• Bleeding Thrombosis
• Clotting factors Natural anticoagulant
• platelets

34
Clot formation

• Platelet activation Primary
  hemostasis
• No count
  (immediate)
• Fibrin generation
• plasma clotting Secondary
  hemostasis
• factors (delayed)

35
Platelet Activation
COLLAGEN
THROMBIN

ADP
GpIIb/IIIa
Platelet
GpIb
Adrenaline
Adhesion
36
Clotting factor production

• Liver source of plasma clotting factors
• except VWF
• Factor VIII produced by liver
• endothelium
• VWF endothelial cells megakaryocytes
• Vitamin K dependent clotting factors are
• II, VII, IX, X

37
COAGULATION PATHWAYS

• Intrinsic extrinsic pathways
• conclude in the common pathway
• Intrinsic pathway clotting factors
• Extrinsic pathway clotting factors
• Common pathway clotting factors

38
Intrinsic pathway XII ---gt XIIa
XI---------XIa
IX --------gt IXa
VIII APC PC PS Ca
PL X----------------------gt Xa Common pathway
VCaPL Prothrombin
-------------gt thrombin AT
v fibrinogen--------------gt fibrin
39
Activation of fibrinolysis
thrombin
damaged cells
inflammation
mental/physical stress
trauma
PAI
t-PA
extrinsic pathway
plasminogen
plasmin
???antiplasmin
cross-linked fibrin
fibrinogen
X-FDP (D-Dimer, cross-linked oligomers, DD/E ...)
FDP (X,Y,D,E)
40
Generation Of Fibrin and D-Dimer
fibrinogen
E
thrombin
fibrin
FpA, FpB
fibrin polymer
F XIIIa
cross-linked fibrin (clot)
D-dimer cross-linkage
41
D-Dimer

• D-Dimer is a synonym for a variety of
  cross-linked fibrin degradation products.
• Indicative for dissolution of an existing
  thrombus.
• Evidence of a previous thrombotic event

42
Clinical Application Of D-Dimer

• Exclusion of deep vein thrombosis (DVT)
• Exclusion of pulmonary embolism (PE)
• Supports diagnosis and monitoring of DIC

43
Incidence Of Venous Thromboembolism

• Annual frequency per 100,000
• Deep vein thrombosis
  160
• Symptomatic, non-fatal PE 20
• Fatal, autopsy-detected PE 50
• 250,000 hospitalisations annually due to VTED
• 
  Int Angiol 1997

44
Complications

• Risk of recurrence 2 years 17.5
• 5 years 24.6
• Fatal PE 150,000 pa
  
• 20-30 PM
• Commonest cause of death in pregnancy
• Post-phlebitic syndrome 3 years after DVT
  35- 69 5-10 years after DVT
  49-100Venous ulcers

45
Mortality From Pulmonary Embolism

• About 1/10 hospital deaths is due to PE
• PE is still the leading cause of maternal
  mortality

46
Diagnosis Of DVT

• Compression ultrasound (CUS)
• Sensitivity 97
• Specificity 94
• Problems
• Calf vein thrombosis sensitivity
• Previous thrombosis specificity Combine
  with D-Dimer and PTP

47
Clinical Prediction Rule

• Entire leg tenderness along deep veins
• collateral superficial veins
• Entire leg swelling
• Calf swelling gt3 cm difference
• Dilated superficial veins
• Pitting edema

48
Clinical Prediction Rule

• Recent bed ridden gt3 days
• Major surgery within last 3 ms.
• Active cancer within last 6 mo.
  
• Plaster
• Paralysis
• Presence of alternative Diagnosis -2

49
Diagnostic Strategies for First Attackproximal
Deep Venous Thrombosis
High probability
Moderate-Low probability (gt3)

(1-2)
(0) Doppler US

D-Dimers Abnormal Normal
Normal
High

Doppler US
Venography
Normal Abnormal
Normal Abnormal Save to
withhold treatment

Treat with heparin
50
Diagnostic Strategies for First AttackDistal
Deep Venous Thrombosis
High probability
Moderate-Low probability (gt3)

(1-2) (0) Doppler US

D-Dimers Abnormal Normal
High
Normal
Doppler US
Repeat in W or venography
Normal abnormal



Abnormal
Normal
Save to withhold treatment
withhold treatment

Treat with heparin
51
Acute VTE

• The usual management consists of UFH or LMWH
  followed by warfarin.
• Heparin is continued for at least 5 days or
  untill INR is in the therapeutic range.
• Warfarin can be started within the first 24h.

52
Heparin

• Mechanism of action augments anti-thrombin
  action ATT 11 ?Heparin ATT 11000
• T ½ 90m
• Dose loading 80U/Kg IV
• maintenance 18U/Kg/h
• Route of administration IV/SC
• Duration 3-5d DVT
• 7-10d PE

53
Heparin

• Monitoring APTT1.5-2.5 X control
• 4-6 h
• Reversal stop heparin
• protamine sulphate 1U
  neutralize
• 100 IU heparin
• No FFP
• Side effects Bleeding
• osteoporosis
• HIT

54
Heparin

• Contraindications congenital bleeding
• disorders
• HIT
• Recent eye or CNS
  operation

55
LMWH

• Dose brand dependent
• Mechanism of action anti-X gt anti-II
• Route of administration IV or S/C
• Monitoring not indicated
• Indication for monitoring pregnancy ,morbid
  obesity , sever renal or liver derangement
• Duration 3-5 d DVT
• 7-10 d PE
• Reversal stop heparin
• protamine sulphate
  un-predictable response

56
LMWH

• Contra-indications PMH HIT
• CNS eye
  operations
• Inherited bleeding disorders
• Side effect less HIT , bleeding osteoporosis.

57
Warfarin

• Mechanism of action Vit K antagonist
• Vit K gamma carboxylation as a post translation
  modification
• Pro-coagulant
  X,IX,VIIII(1972)
• Natural anticoagulant PC PS
• T1/2 PC is shorter than FVII ?temporary
  hyper-coagulable state
• Dose 5 mg P.O
• Route of administration P.O

58
Warfarin

• Monitoring INR
• INR (PT patient/PT control )ISI
• Desired target INR2.5
• INR 3.5 mechanical heart valve , recurrent VTE
  despite proper anti-caogulation ,/- APL
• Side effect bleeding 1/100/y
• ICH 2.5/1000/y
• Warfarin induced skin
  necrosis
• Contra-indications pregnancy (first last
  trimester),Inhetited bleeding disorders ,acute
  stage HIT

59
Thrombophilia
A disorder of the haemostatic mechanism with a
predisposition towards thrombosis BUT Many
patients with defects remain asymptomatic
despite multiple challenges AND gt50 patients
with TED will have no identifiable laboratory
abnormality AND proven thrombophilic defect and
a family history of TED are at greater risk of
TED than individuals with no family history but a
similar defect
60
Thrombophilia

• Thrombosis is a multi-factorial disease
• Multiple genetic risk factors increase the risk
  of TED
• In the majority screen for only the common
  inherited/acquired prothrombotic abnormalities
  Patients with spontaneous venous thromboses, or
  of a severity that is out of proportion to a
  recognised stimulus
• 50 of patients with TED have no evidence of
  prothrombotic abnormalities

61
Thrombophilia

• Definition abnormal tendency towards excessive
  thrombosis .
• Indications
• VTE below 35-40 Y
• Unprovoked VTE
• VTE at unusual sites
• Life threatening VTE
• Recurrent fetal lose syndrome
• Recurrent first trimester abortions
• Investigating SLE patients
• Recurrent thromboses
• Family history of thrombosis

62
Whom to test?

• Thrombosis at an unusual site
• Unprovoked VTE
• Life threatening VTE
• Age less than 40
• Recurrent thromboses
• Family history of thrombosis
• Recurrent miscarriagesVTE below 35Y
• Recurrent fetal lose syndrome
• Recurrent first trimester abortions
• Investigating SLE patients

63
Inherited Thrombophilia

• 1965 AT mutation identified Egeberg et al
• 1967 Dysfunctional fibrinogen Egeberg et al
• 1981 Protein C Griffin et al
• 1984 Protein S Comp et al
• 1993/4 APCr/FV L Dalhback/Bertina et
  al
• 1996 Prothrombin mutation Poort et
  al

64
Thrombophilia Prevalence
Risk factor Subjects with thrombosis () General population () Relative Risk of Thrombosis
Antithrombin 1 0.2 25-50
Protein C 3 0.3 10-15
Protein S 2-3 0.2 11
Factor V Leiden Hetero 20-50 3-15 3-8/80 Homo
Prothrombin 3' UTR mutation Hetero 6 2 3
65
Other Inherited Risk Factors

• Hyperhomocysteineaemia
• Dysfibrinogenaemias
• Factor VII ?/?
• Heparin Cofactor II
• Factor XII deficiency
• Disordered fibrinolysis
• Elevated PAI-1
• Plasminogen deficiency
• Thrombin Activatable Fibrinolytic Inhibitor (TAFI)

66
Acquired

• Obesity
• Immobility (surgery/trauma)
• OCP/HRT
• Pregnancy/puerperium
• Haemoglobinopathies
• Myeloproliferative syndromes
• Hyperviscosity syndromes
• Cardiac failure

67
Acquired

• Chronic inflammatory disorders
• Klinefelters syndrome
• Behçets syndrome
• Malignancy
• Drug induced (e.g. HIT)
• TTP/HUS
• Nephrotic syndrome
• Protein S deficiency
• Inflammatory bowel disease

68
Anti-phospholipid antibodies
Risk factor Subjects with VTE () General population () RR of Thrombosis
Lupus anticoagulant 3-10 4 11
Anti-cardiolipin antibodies 3-10 4 3.2
OCP 21 6 4.2
Pregnancy 6.2 2.3 2.8
Previous VTED 14 2 8
69
Thrombophilia and Laboratory Testing

• Diagnostic accuracy
• Clinical value of the tests
• Interpretation of results
• Tests frequently requested (and interpreted) by
  individuals who are not specialists in this area
• Laboratories frequently have no clinical
  information relating to the patient

70
Thrombophilia screen

• PC level Functional assay
• PS level Functional assay
• AT level Functional assay
• APCR ratio functional assay correlates with
  genetic study FVL
• Prothrombin gene mutation
• MTHFR
• APS LA functional assay
• Anti-cardilipin antibodies

71
Genetic Testing

• Reliable and reasonably robust
• National External Quality Assurance Schemes
  (NEQAS)
• Some incorrectly identified samples
• APCr low Factor V Leiden mutation confirms
• APCr normal No further testing
• Risk of VTED modest
• Do we seek informed consent for genetic testing?

72
Phenotypic Testing Accuracy

• Enormous variability in results
• NEQAS/ECAT data supports this
• Oral anticoagulants Protein C/S
• Inappropriate to base a diagnosis on a single
  result but how many times ?
• Incorrect information to patients may be falsely
  reassuring or result in inappropriate treatment

73
Antithrombin deficiency

• 24 patients with genotypically proven AT
  deficiency
• Heparin co-factor assay
• IIa substrateCorrectly identified all mutations
• Xa substrateCorrectly diagnosed only 50 cases
• NEQAS thrombophilia Survey March 2000
• Functional AT assays showed significant
  differences depending upon substrate

74
Laboratory Tests
15 heterozygous PC deficient patients had
normal PC activity and 5 normal relatives had
low PC activity
Heterozygotes
Normal relatives
75
Timing Of Thrombophilia

• Avoid acute presentation
• consumption of the natural anticoagulant
• Heparin warfarin therapy interfere with the
  assay
• Best time after D/C of warfarin therapy by 2-4 W
• Any abnormal results should be repeated 4-6W
  apart before labeling patient as thrombophilia

76
Interpretation

• Life threatening episode
• 40-50 of selected patients with VTE have normal
  results despite extensive testing
• APS AT are highly thrombogenic associated
  with high recurrence rate.
• Double heterozygosity high incidence of VTE

77
Immediate Management

• No evidence that anticoagulation is less
  efficient with prothrombotic abnormalities
• Antithrombin deficiency Heparin resistance is
  rare type I can be efficiently anticoagulated ,
  antithrombin concentrates is not usually
  indicated
• PC and PS deficiencyWarfarin induced skin
  necrosis is rare
• Screening prior to initiating OAC therapy
  inappropriate
• LA,severe FXII deficiencyelevated Factor VIII
  levels difficult monitoring UFH

78
Intensity Or Duration Of Anticoagulation

• No randomised prospective studiesCurrent
  data/experience standard oral anticoagulant
  protocols
• No evidence that more intensive regimes or
  extended periods of anticoagulation are required
• BUT - APL/multiple inherited abnormalities
  including may be exceptions
• Risk of recurrence may be increased and extended
  periods of treatment may be required
• OACs Mortality 0.3-0.4
• Major bleed 2-3

79
Aggressive Thromboprophylaxis?

• RR increased but the absolute risk is small
• Thromboprophylaxis
• Asymptomatic No indication
• At-risk individuals high risk periods should
  be given
• Economy Class syndrome 90 have gt2 risk
  factors for thrombosis

80
Prothrombotic Abnormality OCP

• Thrombosis in women with inherited prothrombotic
  OCP is increased
• Family studies may be of value in establishing
  the risk of thrombosis if a genetic risk factor
  has been identified
• POP or progestagen-containing IUDs no increased
  risk of VTED
• Factor V Leiden OCP
• RR VTED 35/50-fold increase

81
Prothrombotic Abnormality OCP

• Avoid
• In women with history of TED
• 1st-degree relative with TED
• in women with multiple genetic defects
• Asymptomatic women with identified genetic risk
  factors - not absolute contraindication OCP

82
Prothrombotic Abnormality HRT

• HRT increases risk of TED 3-fold
• Risk highest in the initial 12 ms of treatment
• Synergy between HRT and thrombophilia
• Use with caution in women with a PMH of TED
• EVTET study HRT 10.7 incidence of VTED
• Placebo 2.3
• Asymptomatic women with identified genetic risk
  factors - not an absolute contraindication to HRT

83
Thromboprophylaxis In Pregnancy

• Risk of VTED increased in pregnancy
• Genetic risk factor
• Multiple pregnancy
• Advanced maternal age
• Prolonged bed-rest
• Previous thrombotic history
• Recurrent miscarriages
• Routine thromboprophylaxis is not indicated in
  all women with thrombophilia

84
Thrombophilia Arterial Disease

• No good evidence
• Anti-phospholipid syndrome
• Hyperhomocysteineaemia
• Factor V Leiden/Prothrombin mutation - Possible
  synergistic interaction with other risk factors

85
Summary

• Increasing enthusiasm for thrombophilia testing
• Concerns about accuracy and interpretation
• Lack of evidence-based data to aid management
• Are we providing patients and clinicians with
  inaccurate information that leads to false
  reassurance or alternatively creates panic and
  results in inappropriate treatment?

86

• Genetic defect NO TED
• TED 50 No lab abnormality
• Lab abnormality FH gtlab with NO FH

87
Other Inherited Risk Factors

• Histidine rich glycoprotein
• Elevated FVIII/FX/FXI
• Thrombomodulin mutations
• EPCR mutations
• Tissue Factor Pathway Inhibitor (TFPI)
• Factor V Cambridge
• Factor XIII (Val234Leu)
• Platelet glycoprotein receptor polymorphisms

88
Diagnosis Of DVT/PE

• Development and validation of structured clinical
  assessment for estimating pre-test probability
  (PTP)
• Advances in availability of sensitive and rapid
  turnaround assays for D-Dimer
• Integration of the two above advances into a
  diagnostic, safe algorithm for non-invasive
  objective testing, reducing the need for invasive
  procedures

89
Pre-test probability (PTP) for PEaccording to
Wells 1997
score clinical symptoms / signs of
DVT 3.0 active cancer treated within last 6
months 1.0 heart rate gt 100/min
1.5 immobilization / surgery in last 4 weeks
1.5 previous history of DVT or
PE 1.5 hemoptysis 1.0 no alternative diagnosis
(more) likely than PE 3.0
90
Strategy in diagnosis of PE

• low pre-test probability (PTP) and negative
  D-Dimer, VQ scan negative or non-diagnostic P
  E excluded
• high PTP and diagnostic VQ scan PE
  confirmed
• in any other case
• further testing by
  CUS and /or angiography SD Chunial, JS Ginsberg
  Throm Res 2000

91
Anti-thrombin deficiency

• Resistant to heparin.
• Heparin lower AT level by 30.
• AT conc is safe effective.
• Recommended
• Difficult to achieve adequate anticoagulation .
• Recurrent thrombosis despite adequate
  anticoagulation.
• Thromboprphylaxis when anticoagulation is
  contraindicated.

92
Anti-thrombin deficiency

• AT conc pooled normal human plasma.
• recombinant AT .
• Dose 50 units /Kg .
• Plasma monitoring plasma level gt80.
• Repeat 60 of the initial dose 24h.
• The biological t1/2 2-4 days.

93
Protein C deficiency

• Warfarin induced skin necrosis rare.
• Warfarin reduce PC by 50.
• Routine measurement of plasma PC before starting
  OAC is not recommended.
• Known cases of PC deficiency should receive OAC
  under heparin increased gradually.
• PC conc or FFP can provide protection against
  recurrent skin necrosis until a stable level of
  anticoagulation is achieved.

94
Long term therapy to prevent recurrence

• Recurrence in the first year is 27.Kearon 3m
  Vs extended anticoagulation favours extended
• The lowest recurrence found after 6-12 m of
  initial therapy .
• Long term warfarin is highly effective in
  preventing recurrence as compared with 6 m
  therapy(2.6Vs21) this benefit is partially
  counterbalanced by a trend towered an increased
  incidence of major bleeding (8 Vs3 )no
  difference in mortality .

95
The cumulative incidence of recurrence after of
cessation OAC

Prandoni.
96
Risk of recurrence

• FVL PG mutation heterozygosity conflicting
  reports.
• Number of major bleeding would exceed the number
  of clinically PE that would be prevented
• Combined heterozygosity for FVL PG20210 the
  recurrence rate is significantly high .
• important risk factors homozygous FVL, APS
  cancer.
• PCPS deficiency Low frequency to draw firm
  conclusion.

97
The decision to continue anticoagulation

• Risk of recurrence.
• Risk of major bleeding .
• Patient compliance preference.
• Life expectancy.
• Quality of life.

98
Recommendations .

• Indefinite anticoagulation at target INR 2-3 is
  recommended only in the following high risk
  patients
• Two or more spontaneous thrombosis.
• One spontaneous thrombosis in case of AT
  deficiency or APS.
• One spontaneous life threatening thrombosis
  (near fatal PE ,cerebral, mesenteric ,or portal
  vein thrombosis).
• One spontaneous thrombosis at an unusual site
  (mesenteric ,cerebral).
• One Spontaneous thrombosis in the presence of
  more than a single genetic defect.

99
Future approaches

• Extended low intensity warfarin at INR 1.5-2.
• The PREVENT study low intensity warfarin reduce
  the rate of recurrence by more than 60 compared
  with placebo without an increased in major
  bleeding.
• Ximelagatran was compared to placebo was shwoen
  to be highly effective in preventing recurrent
  VTE.

100
surgery

• Inherited thrombophilia surgery
• Are high risk group .
• Prophylactic perioperative anti-coagulation LMWH.